Processes for preparing optically active alcohols and optically active amines

ABSTRACT

A process for preparing an optically active alcohol by reacting a prochiral ketone corresponding to the optically active alcohol and an acid with a mixture of (1) a boron-containing compound selected from the group consisting of i) a borane compound which is obtained from an optically active β-aminoalcohol and a boron hydride; or obtained from the optically active β-aminoalcohol, a metal borohydride and an acid and ii) an optically active oxazaborolidine and (2) a metal borohydride; and a process for preparing an optically active amine by reacting an oxime derivative and an acid with a mixture of (1) a boron-containing compound selected from the group consisting of i) a borane compound which is obtained from an optically active β-aminoalcohol and a boron hydride, or obtained from said optically active β-aminoalcohol, a metal borohydride and an acid and ii) an optically active oxazaborolidine, and (2) a metal borohydride.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for preparing an opticallyactive alcohol and a process for preparing an optically active amine.

2. Description of the Related Art

As a process for preparing an optically active alcohol, for example,there is known a process comprising reacting an optically activeβ-aminoalcohol and a borane in an amount of two moles per one mole ofsaid aminoalcohol, and then reacting a prochiral ketone in an amount of0.8 mole per one mole of said aminoalcohol with a reaction product (see,for example, J. Chem. Soc. PERKIN TRANS. I., 2039 (1985)).

However, this process has a drawback that a large amount of theexpensive borane should be used.

To solve such drawback, JP-A-7-109231 discloses a process for preparingan optically active alcohol using a metal borohydride which is cheap andeasily available in an industrial scale, that is, a process comprisingreacting a mixture of a 2-substituted oxazaborolidine havingsubstituents on a boron atom and a metal borohydride with an acid, andthen reacting a prochiral ketone with a reaction product to obtain anoptically active alcohol. But, an optical purity of the producedoptically active alcohol is unsatisfactory, and further improvement ofthe process has been desired.

As a process for preparing an optically active amine, there is proposeda process comprising reacting an optically active β-aminoalcohol with aborane, and then reacting a syn or anti-form of an oxime derivative witha reaction product, whereby an optically active amine having a desiredabsolute configuration is prepared (see JP-A-63-99041 and TetrahedronLett., 29223 (1988).

However, this process has a drawback that a large amount of an expensiveborane should be used.

To solve such drawback, JP-A-2-311446 and JP-A-5-9158 disclose a processfor preparing an optically active amine using a metal borohydride whichis cheap and easily available in an industrial scale, that is, a processcomprising reacting an optically active β-aminoalcohol with a metalborohydride and an acid, and then reacting an oxime derivative with areaction product.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a process for preparingan optically active alcohol having an increased optical purityeffectively even in an industrial scale while reducing an amount of aused metal borohydride or boron hydride as a hydrogen source.

Another object of the present invention is to provide a process forpreparing an optically active amine having an increased optical purityeffectively even in an industrial scale while reducing an amount of aused metal borohydride or boron hydride as a hydrogen source.

According to a first aspect of the present invention, there is provideda process for preparing an optically active alcohol comprising reactinga prochiral ketone which corresponds to the optically active alcohol andan acid with a mixture which comprises

(1) a boron-containing compound selected from the group consisting of

i) a borane compound which is obtained from an optically activeβ-aminoalcohol of the formula (I): ##STR1## wherein R¹ is a hydrogenatom, a lower alkyl group or an aralkyl group which may have at leastone substituent, R², R³, R⁴ and R⁵ represent independently each other ahydrogen atom, a lower alkyl group, an aryl group which may have atleast one substituent, or an aralkyl group which may have a substituent,provided that R⁴ and R⁵ are different, that R³ and R⁵ may together forma lower alkylene group, or that R³ and R⁴ may together form a loweralkylene group which may have optionally a substituent or with which abenzene ring is condensed, and * stands for an asymmetric carbon atom,and a boron hydride; or obtained from said optically activeβ-amino-alcohol (II), a metal borohydride and an acid, and

ii) an optically active oxazaborolidine of the formula (II): ##STR2##wherein R¹, R², R³, R⁴, R⁵ and * are the same as defined above, and R⁶is a hydrogen atom, a halogen atom, an alkyl group which may besubstituted by at least one halogen atom, an aryl group which may haveat least one substituent or an aralkyl group which may have at least onesubstituent, and

(2) a metal borohydride.

According to a second aspect of the present invention, there is provideda process for preparing an optically active amine of the formula:(III):##STR3## wherein R⁷ and R⁸ are different and represent an alkyl groupwhich may have at least one substituent, an aryl group which may have atleast one substituent or an aralkyl group which may have at least onesubstituent, or R⁷ and R⁸ form, together with the carbon atom bonded tothe amino group, a ring or condensed ring which may have a hetero atom,and * is the same as defined above comprising reacting an oximederivative of the formula (IV): ##STR4## wherein R⁷ and R⁸ are the sameas defined above, and R⁹ is an alkyl group, an aralkyl group or analkyl-substituted silyl group and an acid with a mixture which comprises

(1) a boron-containing compound selected from the group consisting of

i) a borane compound which is obtained from an optically activeβ-aminoalcohol of the formula (I) and a boron hydride, or obtained fromsaid optically active β-aminoalcohol (I), a metal borohydride and anacid, and

ii) an optically active oxazaborolidine of the formula (II) and (2) ametal borohydride.

The oxime derivative (IV) may be a syn-form, an anti-form or a mixturethereof which is rich in one of them.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of a mixture of a borane compound and metal borohydride

R¹ in the optically active β-aminoalcohol of the formula (I) is ahydrogen atom, a straight or branched lower alkyl group having usually 1to 8 carbon atom, preferably 1 to 5 carbon atoms (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl,etc.), or an aralkyl group having usually 7 to 15 carbon atom,preferably 7 to 12 carbon atoms (e.g. benzyl, phenethyl, methylbenzyl,etc.) which may be substituted with a lower (C₁ -C₅) alkyl or alkoxygroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec.-butyl, tert.-butyl, pentyl, methoxy, ethoxy, propoxy, butoxy,pentoxy, etc.).

R², R³, R⁴ and R⁵ represent independently each other a hydrogen atom, alower alkyl group having usually 1 to 8 carbon atom, preferably 1 to 5carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec.-butyl, tert.-butyl, pentyl, etc.), an aryl group having 6to 12 carbon atoms, preferably 6 to 11 carbon atoms (e.g. phenyl,1-naphthyl, 2-naphthyl, etc.), or an aralkyl group having usually 7 to12 carbon atoms (e.g. benzyl, phenethyl, methylbenzyl, etc.). The arylor aralkyl group may be substituted with a lower alkyl or alkoxy groupwhich may be the same as exemplified above. R⁴ and R⁵ are not the same.R¹ and R⁵ may together form a lower alkylene group such as methylene,dimethylene, trimethylene, tetramethylene, etc. R³ and R⁴ may togetherform a lower alkylene group which may have optionally a substituent orwith which a benzene ring is condensed, such as trimethylene,tetramethylene, pentamethylene, o-phenylenemethylene,o-phenylenedimethylene, etc.

Specific examples of the optically active β-aminoalcohol (I) areoptically active norephedrine, ephedrine,2-amino-1-(2,5-dimethylphenyl)-1-propanol,2-amino-1-(2,5-dimethoxyphenyl)-1-propanol,2-amino-1-(2,5-diethoxyphenyl)-1-propanol,2-amino-1-(2,5-dipropoxyphenyl)-1-propanol,2-amino-1-(2-methoxyphenyl)-1-propanol,2-amino-1-(2-ethoxyphenyl)-1-propanol,2-amino-1-(2-propoxyphenyl)-1-propanol,2-amino-1-(2-methylphenyl)-1-propanol,2-amino-1-(2-methoxy-5-methylphenyl)-1-propanol,2-amino-1-(4-methoxy-2-methylphenyl)-1-propanol,2-amino-1-(2-ethoxy-5-methylphenyl)-1-propanol,2-amino-1-(2,4-dimethylphenyl)-1-propanol,2-amino-1-(2,4,6-trimethylphenyl)-1-propanol,2-amino-1-(1-naphthyl)-1-propanol, 2-amino-1-(2-naphthyl)-1-propanol,2-amino-1,2-diphenylethanol, 2-amino-1,1-diphenyl-1-propanol,2-amino-1,1-diphenyl-3-methyl-1-butanol,2-amino-1,1-diphenyl-4-methyl-1-propanol,2-amino-1,1-diphenyl-1-butanol, 2-amino-1,1,3-triphenyl-1-propanol,2-amino-1,1,2-triphenyl-1-ethanol, 2-amino-3-methyl-1-butanol,2-amino-4-methyl-1-pentanol, 2-amino-1-propanol,2-amino-3-phenyl-1-propanol, 2-amino-2-phenyl-1-ethanol, etc., and theirN-lower alkyl or N-aralkyl derivatives; 2-pyrrolidinemethanol,α,α-diphenyl-2-pyrrolidinemethanol, 2-piperidinemethanol,α,α-diphenyl-2-piperidinemethanol, 2-aziridinemethanol,α,α-diphenyl-2-azetizinemethanol, 2-azetizinemethanol,α,α-diphenyl-2-azetizinemethanol, 2-aminocyclopentan-1-ol,2-aminocyclohexan-1-ol, 1-aminoindan-2-ol, and so on.

Examples of the boron hydride are diborane, borane-tetrahydrofurancomplex, borane-dioxane complex, borane-dimethylsulfide complex,borane-thioxane complex, and so on.

Examples of the metal borohydride are lithium borohydride, sodiumborohydride, potassium borohydride, zinc borohydride, and so on. Amongthem, sodium borohydride is preferred.

The metal borohydride used in the preparation of the borane compound andthat used in the reduction of the prochiral ketone or the oximederivative (IV) are usually the same, while they may be different.

Examples of the acid are Br.o slashed.nsted acids such as sulfuric acid,acetic acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonicacid, hydrogen chloride, etc.; and Lewis acids such as zinc chloride,boron trifluoride, aluminum chloride, aluminum bromide, titaniumtetrachloride, tin tetrachloride, tin trichloride, iodine, etc.

The acid used in the preparation of the borane compound and that used inthe reduction of the prochiral ketone or the oxime derivative (IV) areusually the same, while they may be different.

The preparation of the borane compound and the reduction of theprochiral ketone or the oxime derivative (IV) are usually performed inthe presence of a solvent. The solvent used in the preparation of theborane compound and that used in the reduction of the prochiral ketoneor the oxime derivative (IV) are usually the same, while they may bedifferent.

Examples of the solvent are ethers (e.g. dioxane, 1,3-dioxolane,tetrahydrofuran, diglyme, etc.), sulfides (e.g. dimethylsulfide,diethylsulfide, etc.), and mixtures thereof, and mixtures of the abovesolvent and a hydrocarbon (e.g. benzene, toluene, xylene, chlorobenzene,1,2-dichloroethane, etc.).

An amount of the solvent is usually from 1 to 50 times the weight of theprochiral ketone or the oxime derivative (IV).

In the preparation of the borane compound, in general, the boron hydrideis added to the mixture of the optically active β-aminoalcohol (I) andthe solvent, or the acid is added to the mixture of the optically activeβ-aminoalcohol (I), the metal borohydride and the solvent. The boronhydride or the acid may be used as a mixture in the solvent.

In general, the boron hydride or the metal borohydride is used in anamount of 0.8 to 2 moles in terms of the boron atom per one mole of theoptically active β-aminoalcohol (I). When the metal borohydride is used,it may be added, at this stage, in an amount sufficient for performingthe reaction with the optically active β-aminoalcohol (I) and also thereduction of the prochiral ketone or the oxime derivative (IV). Themetal borohydride is more preferably used than the boron hydride.

The acid is used usually in an amount of 0.8 to 2.1 equivalents of theoptically active β-aminoalcohol (I).

In general, an amount of the metal borohydride which contributes to thesynthesis of the borane compound is determined by the amount of theacid. Theoretically, an excessive portion of the metal borohydride inrelation to the acid will form a mixture with the borane compound.

A temperature at which the boron hydride is added is usually from -20°to +100° C., preferably from 0° to 80° C. After the addition of theboron hydride, the reaction mixture is preferably stirred at the sametemperature for 0.1 to 20 hours.

A temperature at which the acid is added is usually from -20° to +100°C., preferably from 0° to 80° C. After the addition of the acid, thereaction mixture is preferably stirred at the same temperature for 0.1to 10 hours.

In the reduction of the prochiral ketone, an amount of the opticallyactive β-aminoalcohol (I) is usually from 0.005 to 0.5 mole, preferablyfrom 0.01 to 0.4 mole per one mole of the prochiral ketone. In thereduction of the oxime derivative (IV), an amount of the opticallyactive β-aminoalcohol (I) is usually from 0.01 to 1.1 moles, preferablyfrom 0.01 to 0.9 mole, more preferably 0.03 to 0.9 mole per one mole ofthe oxime derivative (IV).

In a case where the metal borohydride is added in the preparation stepof the borane compound in an amount sufficient for performing thereaction with the optically active β-aminoalcohol (I) and also thereduction of the prochiral ketone or the oxime derivative (IV), themixture of the borane compound and the metal borohydride is obtained,while, in other case, such mixture is obtained by the addition of themetal borohydride to the resulting borane compound.

When the metal borohydride is additionally added, an amount of the metalborohydride in the mixture with the borane compound is usually from 0.3to 3 moles, preferably from 0.5 to 2 moles in terms of the boron atomper one mole of the prochiral ketone in the case of the reduction of theprochiral ketone. The reaction proceeds sufficiently when this amount isfrom 0.5 to 1 mole. In the case of the reduction of the oximederivative, the additional amount of the metal borohydride is usuallyfrom 0.5 to 2.1 moles, preferably from 0.8 to 1.5 moles in terms of theboron atom per one mole of the oxime derivative (IV).

Preparation of a mixture of a optically active oxazaborolidine (II) anda metal borohydride

Examples of the alkyl, aralkyl and aryl groups for R¹, R², R³, R⁴ andR⁵, and examples of the alkylene group formed from R¹ and R⁵ or R³ andR⁴ in the optically active oxazaborolidine (II) are the same as thoseexemplified in connection with the optically active β-aminoalcohol (I).

Examples of the lower alkyl group for R⁶ are the same as those for R²and so on, that is, an alkyl group having usually 1 to 8 carbon atomswhich may be substituted with 1 to 6 halogen atoms (e.g. hexyl,cyclohexyl, heptyl, 2-ethylhexyl, octyl, 1-chloroethyl, 1-bromoethyl,1-fluoroethyl, 2-fluoroethyl, 3-chloropropyl, 3,3,3-trifluoropropyl.Examples of the aryl group are an aryl group having usually 6 to 12carbon atoms, preferably 6 to 10 carbon atoms (e.g. phenyl, 1-naphthyl,2-naphthyl, etc.), an aryl group substituted with at least one alkylgroup having usually 1 to 8 carbon atoms (e.g. o-, m- or p-methylphenyl,o-, m- or p-ethylphenyl, o-, m- or p-butylphenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dimethylphenyl, etc.), an aryl group substituted withat least one alkoxy group having usually 1 to 8 carbon atoms (e.g. o-,m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-propoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl,etc.), an aryl group substituted with at least one halogen atom (e.g.o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- orp-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6-, or 3,4,5-trifluorophenyl, etc.),an aryl group substituted with at least one halogen atom and at leastone alkyl group (e.g. 4-bromo-3,5-dimethylphenyl,4-bromo-2,6-dimethylphenyl, 4-fluoro-3,5-dimethylphenyl, etc.), an arylgroup substituted with at least one halogen atom and at least one alkoxygroup (e.g. 2-chloro-5-methoxyphenyl, 2-bromo-5-methoxyphenyl,2-fluoro-5-methoxyphenyl, 3-bromo-5-methoxyphenyl,4-ethoxy-2,3-difluorophenyl, etc.), and an aryl group substituted with ahalogenated alkyl group (e.g. 2-(chloromethyl)phenyl,2-(bromomethyl)phenyl, 2-(fluoromethyl)phenyl,3-(trifluoromethyl)phenyl, o-, m- or p-(1-chloroethyl)phenyl, o-, m- orp-(1-bromoethyl)phenyl, o-, m- or p-(3-chloropropyl)phenyl,2-bromomethyl-6-methylphenyl, etc.). Examples of the aralkyl group arean aralkyl group having usually 7 to 12 carbon atoms, preferably 7 to 10carbon atoms (e.g. benzyl, etc.), an aralkyl group substituted with atleast one alkyl or alkoxy group having 8 to 13 carbon atoms (e.g. o-, m-or p-tolylmethyl, o-, m- or p-ethylbenzyl, o-, m- or p-methoxybenzyl,o-, m- or p-ethoxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dimethylbenzyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dimethylphenyl)ethylalkyl. Examples of the halogen atom arefluorine, chlorine and bromine.

Specific examples of the optically active oxazaborolidine (II) areoptically active 1,3,2-(4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2,4-dimethyl-5-phenyl)oxazaborolidine,1,3,2-(2-ethyl-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-propyl-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-butyl-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(4-methyl-2,5-diphenyl)oxazaborolidine,1,3,2-(2-(o-fluorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(m-fluorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(p-fluorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,4-difluorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,5-difluorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,6-difluorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2-chlorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(3-chlorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,3-dichlorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,6-dichlorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(3,5-dichlorophenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(o-methoxyphenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(m-methoxyphenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(p-methoxyphenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,5-dimethoxyphenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(o-tolyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(m-tolyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(p-tolyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(2-(2,5-dimethylphenyl)-4-methyl-5-phenyl)oxazaborolidine,1,3,2-(4,5-diphenyl)oxazaborolidine,1,3,2-(2-methyl-4,5-diphenyl)oxazaborolidine,1,3,2-(2-methyl-4,5-di(2-naphthyl)oxazaborolidine,1,3,2-(4,5-di(2-naphthyl))oxazaborolidine,1,3,2-(2-methyl-4-(2-methylpropyl)-5-phenyl)oxazaborolidine,1,3,2-(4-(2-methylpropyl)-5-phenyl)oxazaborolidine,1,3,2-(2-methyl-4-(1-methylpropyl)-5-phenyl)oxazaborolidine,1,3,2-(4-(1-methylpropyl)-5-phenyl)oxazaborolidine,1,3,2-(2-methyl-4-(1-methylethyl)-5-phenyl)oxazaborolidine,1,3,2-(4-(1-methylethyl)-5-phenyl)oxazaborolidine,1,3,2-(2-methyl-4-(1,1-dimethylethyl)-5-phenyl)oxazaborolidine,1,3,2-(4-(1,1-dimethylethyl)-5-phenyl)oxazaborolidine,1,3,2-(2-methyl-4-(phenylmethyl)-5-phenyl)oxazaborolidine,1,3,2-(4-(phenylmethyl)-5-phenyl)oxazaborolidine,1,3,2-(2-methyl-4-(phenyl-5-(p-tolyl))oxazaborolidine,1,3,2-(4-phenyl-5-(p-tolyl))oxazaborolidine,1,3,2-(2,4-dimethyl-5-(2,5-dimethylphenyl))oxazaborolidine,1,3,2-(4-methyl-5-(2,5-dimethylphenyl))oxazaborolidine,1,3,2-(2,4-dimethyl-5-(2,5-dimethoxyphenyl))oxazaborolidine,1,3,2-(4-methyl-5-(2,5-dimethoxyphenyl))oxazaborolidine,1,3,2-(2-methyl-4-phenyl)oxazaborolidine,1,3,2-(4-phenyl)oxazaborolidine, 1,3,2-(2,4-diphenyl)oxazaborolidine,1,3,2-(2,4-dimethyl)oxazaborolidine, 1,3,2-(4-methyl)oxazaborolidine,1,3,2-(4-ethyl)oxazaborolidine, 1,3,2-(2-methyl-4-ethyl)oxazaborolidine,1,3,2-(4-propyl)oxazaborolidine,1,3,2-(2-methyl-4-propyl)oxazaborolidine,1,3,2-(4-isopropyl)oxazaborolidine,1,3,2-(2-methyl-4-isopropyl)oxazaborolidine,1,3,2-(2-methyl-4-(1-methylpropyl))oxazaborolidine,1,3,2-(4-(1-methylpropyl))-oxazaborolidine,1,3,2-(2-methyl-4-(2-methylpropyl))oxazaborolidine,1,3,2-(4-(2-methylpropyl))oxazaborolidine,1,3,2-(2-methyl-4-(tert.-butyl))oxazaborolidine,1,3,2-(4-(tert.-butyl))oxazaborolidine,1,3,2-(2-methyl-4,5,5-triphenyl)oxazaborolidine,1,3,2-(4,5,5-triphenyl)oxazaborolidine, 1,3,2-(4-benzyl)oxazaborolidine,1,3,2-(2-methyl-4-benzyl)oxazaborolidine,1,3,2-(2-methyl-4-benzyl-5,5-diphenyl)oxazaborolidine,1,3,2-(4-benzyl-5,5-diphenyl)oxazaborolidine,1,3,2-(4-methyl-5,5-diphenyl)oxazaborolidine,1,3,2-(4-isopropyl-5,5-diphenyl)oxazaborolidine,1,3,2-(4-isobutyl-5,5-diphenyl)oxazaborolidine,1,3,2-(2,4-dimethyl-5,5-diphenyl)oxazaborolidine,1,3,2-(4-isopropyl-2-methyl-5,5-diphenyl)oxazaborolidine,1,3,2-(4-isobutyl-2-methyl-5,5-diphenyl)oxazaborolidine,1,3,2-(2,5,5-trimethyl-4-(tert.-butyl))oxazaborolidine,1,3,2-(5,5-dimethyl-4-(tert.-butyl))oxazaborolidine,1,3,2-(2,4-dimethyl-5,5-di(o-methylphenyl))oxazaborolidine,1,3,2-(4-methyl-5,5-di(o-methylphenyl))oxazaborolidine,1,3,2-(2,4-dimethyl-5,5-dibenzyl)oxazaborolidine,1,3,2-(4-methyl-5,5-dibenzyl)oxazaborolidine,1,3,2-(2,4-dimethyl-5,5-di(p-methoxyphenyl)oxazaborolidine,1,3,2-(4-methyl-5,5-di(p-methoxyphenyl)oxazaborolidine,3,4-propano-1,3,2-oxazaborolidine,5,5-diphenyl-3,4-propano-1,3,2-oxazaborolidine,2-methyl-5,5-diphenyl-3,4-propano-1,3,2-oxazaborolidine,2-methyl-3,4-propano-1,3,2-oxazaborolidine,2-ethyl-3,4-propano-1,3,2-oxazaborolidine,5,5-diphenyl-3,4-ethano-2-methyl-1,3,2-oxazaborolidine,3,4-butano-5,5-di(p-tolyl)-2-methyl-1,3,2-oxazaborolidine, and so on.

The optically active oxazaborolidine (II) can be prepared by reactingthe optically active β-aminoalcohol (I) with a boronic acid of theformula (V):

    R.sup.6 --B(OH).sub.2                                      (V)

wherein R⁶ is the same as define above, or with a boroxine derivative ofthe formula (VI): ##STR5## wherein R⁶ is the same as defined above.

Examples of the groups for R⁶ in the formulas (V) and (IV) are the sameas those exemplified above.

Specific examples of the boronic acid (V) are boronic acid,methylboronic acid, ethylboronic acid, propylboronic acid, butylboronicacid, pentylboronic acid, hexylboronic acid, phenylboronic acid, α,β-naphthylboronic acid, o-, m- or p-methylphenylboronic acid, 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenylboronic acid, mesitylboronicacid, o-, m- or p-fluorophenylboronic acid, o-, m- orp-chlorophenylboronic acid, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenylboronic acid, benzylboronic acid, o-, m- orp-tolylmethylboronic acid, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dimethylbenzylboronic acid, and so on.

Specific examples of the boroxine derivative (VI) are trimethylboroxine,triethylboroxine, tripropylboroxine, tributylboroxine,triisobutylboroxine, tripentylboroxine, trihexylboroxine,trioctylboroxine, tris(1-methylethyl)boroxine,tris(1,1-dimethylethyl)boroxine, tris(1-methylpropyl)boroxine,tris(1,1-diethylpropyl)boroxine, tris(1-chloroethyl)boroxine,tris(3-chloropropyl)boroxine, tris(3,3,3-trifluoropropyl)boroxine,triphenylboroxine, tris(2-methylphenyl)boroxine,tris(3-methylphenyl)boroxine, tris(4-methylphenyl)boroxine,tris(2-ethylphenyl)boroxine, tris(3-ethylphenyl)boroxine,tris(4-ethylphenyl)boroxine, tris(2,3-dimethylphenyl)boroxine,tris(2,4-dimethylphenyl)boroxine, tris(2,5-dimethylphenyl)boroxine,tris(2,6-dimethylphenyl)boroxine, tris-(3,4-dimethylphenyl)boroxine,tris(3,5-dimethylphenyl)boroxine, tris(2-methoxyphenyl)boroxine,tris(3-methoxyphenyl)boroxine, tris(4-methoxyphenyl)boroxine,tris(2-ethoxyphenyl)boroxine, tris(2-propoxyphenyl)boroxine,tris(2-chlorophenyl)boroxine, tris(3-chlorophenyl)boroxine,tris(4-chlorophenyl)boroxine, tris(3-bromophenyl)boroxine,tris(3-fluorophenyl)boroxine, tris(4-chlorophenyl)boroxine,tris(4-bromophenyl)boroxine, tris(4-fluorophenyl)boroxine,tris(2,3-difluorophenyl)boroxine, tris(2,4-difluorophenyl)boroxine,tris(2,5-difluorophenyl)boroxine, tris(2,6-difluorophenyl)boroxine,tris(3,4-difluorophenyl)boroxine, tris(3,5-difluorophenyl)boroxine,tris(4-bromo-2,6-dimethylphenyl)boroxine,tris(4-bromo-3,5-dimethylphenyl)boroxine,tris(4-bromo-3,6-dimethylphenyl)boroxine,tris(2-chloro-5-methoxyphenyl)boroxine,tris(2-bromo-5-methoxyphenyl)boroxine,tris(2-fluoro-5-methoxyphenyl)boroxine,tris(5-bromo-2-methoxyphenyl)boroxine,tris(4-chloro-3-methoxyphenyl)boroxine,tris(4-ethoxy-2,3-difluorophenyl)boroxine,tris(2-(chloromethyl)phenyl)boroxine,tris(2-(bromomethyl)phenyl)boroxine,tris(4-(bromomethyl)phenyl)boroxine,tris(o-(1-bromoethyl)phenyl)boroxine,tris(m-(1-bromoethyl)phenyl)boroxine,tris(p-(1-bromoethyl)phenyl)boroxine,tris(p-(1-bromoethyl)phenyl)boroxine,tris(p-(dibromomethyl)phenyl)boroxine,tris(m-(trichloromethyl)phenyl)boroxine,tris(o-(1,2-dibromoethyl)phenyl)boroxine,tris(2-(trifluoromethyl)phenyl)boroxine,tris(3-(trifluoromethyl)phenyl)boroxine,tris(4-(trifluoromethyl)phenyl)boroxine,tris(2-(bromomethyl)-6-methylphenyl)boroxine, tris(phenylethyl)boroxine,trichloroboroxine, tribromoboroxine, and so on.

In the preparation of the optically active oxazaborolidine (II), anamount of the boronic acid (V) is usually from 1 to 5 equivalents,preferably from 1 to 2 equivalents of the optically activeβ-aminoalcohol (I), or an amount of the boroxine derivative (IV) isusually from 0.3 to 1 equivalent, preferably from 0.3 to 0.8 equivalentof the optically active β-aminoalcohol (I).

In general, the above reaction is performed in the presence of asolvent. As the solvent, any aprotic solvent may be used. Examples ofthe solvent are aromatic hydrocarbons such as toluene, benzene,chlorobenzene, etc., aliphatic hydrocarbons such as hexane, heptane,chloroform, dichloroethane, etc., and so on.

A reaction temperature is usually from 0° to +150° C., preferably from10° to 120° C., and a reaction time is usually from 10 minutes to 8hours.

If desired, the optically active oxazaborolidine (II) may be isolatedfrom the reaction mixture by a per se conventional method such asconcentration, distillation, and so on.

In general, the optically active oxazaborolidine (II) and the metalborohydride are mixed in a solvent which is used in the reductionreaction.

An amount of the optically active oxazaborolidine (II) is usually from0.01 to 0.6 mole per one mole of the prochiral ketone, or from 0.05 to0.9 mole per one mole of the oxime derivative (IV).

Preferred examples of the metal borohydride are lithium borohydride,sodium borohydride, potassium borohydride, zinc borohydride, and so on.Among them, sodium borohydride is particularly preferred.

An amount of the metal borohydride is usually at least 0.5 mole,preferably from 0.5 to 1 mole in terms of boron atoms per one mole ofthe prochiral ketone, or usually from 0.5 to 2.5 moles, preferably from0.7 to 2 moles in terms of boron atoms per one mole of the oximederivative (IV).

Preparation of an optically active alcohol through reduction of aprochiral ketone

The optically active alcohol can be prepared by reacting the prochiralketone corresponding to the optically active alcohol and the acid withthe mixture of the metal borohydride and

i) the borane compound prepared from the optically active β-aminoalcohol(I) and the boron hydride, or from the optically active β-aminoalcohol(I), the metal borohydride and the acid, or

ii) the optically active oxazaborolidine (II).

A preferred example of the prochiral ketone is a ketone of the formula:

    R.sup.7 --CO--R.sup.8                                      (VII)

wherein R⁷ and R⁸ are different and represent an alkyl group which mayhave an substituent, an aryl group which may have a substituent, or anaralkyl group which may have a substituent, or R⁷ and R⁸ form, togetherwith a carbon atom of the carbonyl group, a ring or condensed ringoptionally having a hetero atom.

When the reduction reaction is carried out using this prochiral ketone(VII), the corresponding optically active alcohol of the formula (VIII):

    R.sup.7 --C*H(OH)--R.sup.8                                 (VIII)

wherein R⁷ and R⁸ are the same as defined above, and * stands for anasymmetric carbon atom is obtained.

The alkyl group for R⁷ and R⁸ has usually 1 to 6 carbon atoms and isoptionally substituted with at least one halogen atom, and examplesthereof are methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl,cyclohexyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-chloropropyl,4-chlorobutyl, and so on.

Examples of the aryl group for R⁷ and R⁸ are aromatic hydrocarbon groupshaving usually 6 to 15 carbon atoms and optionally at least onesubstituent such as phenyl, 1-naphthyl, 2-naphthyl, etc., andheterocyclic groups such as 2-pyridyl, 3-pyridyl, 4-thiazolyl, etc.

Examples of the substituent which is optionally present on the arylgroup are halogen atoms (e.g. chlorine, bromine, etc.), lower alkylgroups (e.g. methyl, ethyl, propyl, butyl, etc.), lower alkoxy groups(e.g. methoxy, ethoxy, propoxy, etc.), aralkyl groups (e.g. benzyl,etc.), aralkyloxy groups (e.g. benzyloxy, etc.), a cyano group, lowerhaloalkyl groups having 1 to 6 carbon atoms (e.g. fluoromethyl,trifluoromethyl, chloromethyl, trichloromethyl, etc.).

Examples of the substituted aryl group are halogen-substituted phenyl(e.g. o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, 2,3-, 2,4-,2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, etc.), lower alkyl-substitutedphenyl (e.g. o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dimethylphenyl, etc.), lower alkoxy-substituted phenyl (e.g. o-,m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-propoxyphenyl, etc.), benzyloxy-substituted phenyl (e.g. o-, m- orp-benzyloxyphenyl, etc.), cyano-substituted phenyl (e.g. o-, m- orp-cyanophenyl, etc.), 2-trifluoromethyl-4-thiazolyl,2-methyl-4-thiazolyl, and so on.

The aralkyl group has usually 7 to 15 carbon atoms and optionally atleast one substituent, and examples thereof are benzyl, o-, m- orp-tolylmethyl, o-, m- or p-ethylbenzyl, o-, m- or p-methoxybenzyl, o-,m- or p-ethoxybenzyl, and so on.

Examples of the ring or condensed ring formed from R⁷ and R⁸ togetherwith the carbon atom of the carbonyl group are cyclic ketones such ascyclopentenone, cyclohexenone, 1,3-cyclopentanedione,4-cyclopentene-1,3-dione, etc.; hetero atom-containing cyclic ketonessuch as 3-oxopyrrolidine, 3-oxopiperidine, 3-oxo-quinuclidine, andN-alkyl or N-aralkyl derivatives of the above cyclic ketones; indaline,tetralinone, and so on.

Examples of the prochiral ketone (VII) are acetophenone, propiophenone,butyrophenone, 1-acetonaphthone, 2-acetonaphthone,o-methoxyacetophenone, o-ethoxyacetophenone, o-propoxyacetophenone,o-benzyloxyacetophenone, p-tert.-butylacetophenone, 2-acetylpyridine,p-cyanoacetophenone, phenyl benzyl ketone, phenyl o-tolylmethyl ketone,phenyl m-tolylmethyl ketone, phenyl p-tolylmethyl ketone, 2-butanone,2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, cyclohexyl methylketone, cyclohexyl benzyl ketone, 2-chloroacetophenone,2-bromoacetophenone, 2-bromo-3'-chloroacetophenone,2-chloro-3'-chloroacetophenone, 2-bromo-3'-bromoacetophenone,2-bromo-3'-fluoroacetophenone, 2-bromo-3'-methylacetophenone,2-bromo-3'-ethylacetophenone, 2-bromo-3'-propylacetophenone,2-bromo-3'-butylacetophenone, 2-bromo-3'-methoxyacetophenone,2-bromo-3'-ethoxyacetophenone, 2-bromo-3'-propoxyacetophenone,2-bromo-3'-butoxyacetophenone, 2-bromo-4'-chloroacetophenone,2-bromo-4'-bromoacetophenone, 2-bromo-4'-fluoroacetophenone,2-bromo-4'-methylacetophenone, 2-bromo-4'-ethylacetophenone,2-bromo-4'-propylacetophenone, 2-bromo-4'-butylacetophenone,2-bromo-4'-methoxyacetophenone, 2-bromo-4'-ethoxyacetophenone,2-bromo-4'-propoxyacetophenone, 2-bromo-4'-butoxyacetophenone,2-bromo-2'-chloroacetophenone, 2-bromo-2'-bromoacetophenone,2-bromo-2'-fluoroacetophenone, 2-bromo-2'-methylacetophenone,2-bromo-2'-ethylacetophenone, 2-bromo-2'-propylacetophenone,2-bromo-2'-butylacetophenone, 2-bromo-2'-methoxyacetophenone,2-bromo-2'-ethoxyacetophenone, 2-bromo-2'-propoxyacetophenone,2-bromo-2'-butoxyacetophenone, 2-bromo-2'-chloro-3'-methoxyacetophenone,2-bromo-2'-bromo-3'-methoxyacetophenone,2-bromo-2'-fluoro-3'-methoxyacetophenonone,2-bromo-3'-methoxy-2'-methyl-acetophenone,2-bromo-2',3'-dimethoxyacetophenone,2-bromo-2'-ethoxy-3'-methoxyacetophenone,2-bromo-2',3'-dichloroacetophenone,2-bromo-2'-bromo-3'-chloroacetophenone,2-bromo-3'-chloro-2'-fluoroacetophenone, cyclopentenone,1,3-cyclopentandione, cyclohexenone, 4-cyclopenten-1,3-dione,3-oxopyrrolidine, 3-oxopiperidine, 3-oxoquinuclidine, N-alkyl orN-aralkyl derivatives thereof; 2-bromo-3'-chloro-2'-fluoroacetophenone,2-bromo-3'-chloro-2'-methylacetophenone,2-bromo-3'-chloro-2'-methoxyacetophenone,2-bromo-3'-chloro-2'-ethoxyacetophenone,2-bromo-3'-bromo-4'-chloroacetophenone,2-bromo-2',4'-dibromoacetophenone,2-bromo-2'-bromo-4'-fluoroacetophenone,2-bromo-2'-bromo-4'-methylacetophenone,2-bromo-2'-bromo-4'-methoxyacetophenone,2-bromo-4'-chloro-2'-fluoroacetophenone,2-bromo-2',4'-difluoroacetophenone,2-bromo-4'-bromo-2'-fluoroacetophenone,2-bromo-2'-fluoro-4'-methylacetophenone,2-bromo-2'-fluoro-4'-methoxyacetophenone,2-bromo-4'-ethoxy-2'-fluoroacetophenone,2-bromo-4'-chloro-2'-ethoxyacetophenone,2-bromo-4'-bromo-2'-ethoxyacetophenone,2-bromo-4'-fluoro-2'-ethoxyacetophenone,2-bromo-4'-methyl-2'-ethoxyacetophenone,2-bromo-4'-methoxy-2'-ethoxyacetophenone,2-bromo-2',4'-diethoxyacetophenone,2-bromo-4'-chloro-3'-ethoxyacetophenone,2-bromo-4'-bromo-3'-ethoxyacetophenone,2-bromo-4'-fluoro-3'-ethoxyacetophenone,2-bromo-3'-ethoxy-4'-methylacetophenone,2-bromo-3'-ethoxy-4'-methoxyacetophenone,2-bromo-3',4'-diethoxyacetophenone,2-bromo-5'-bromo-3'-chloroacetophenone,2-bromo-3',5'-dibromoacetophenone,2-bromo-5'-bromo-3'-fluoroacetophenone,2-bromo-5'-bromo-3'-methylacetophenone,2-bromo-5'-bromo-3'-methoxyacetophenone,2-bromo-5'-bromo-3'-ethoxyacetophenone,2-bromo-3'-chloro-5'-ethoxyacetophenone,2-bromo-3'-bromo-5'-ethoxyacetophenone,2-bromo-5'-ethoxy-3'-fluoroacetophenone,2-bromo-5'-ethoxy-3'-methylacetophenone,2-bromo-5'-ethoxy-3'-methoxyacetophenone,2-bromo-3',5'-dimethoxyacetophenone, 2-bromo-3',5'-diethoxyacetophenone,2-bromo-3',5'-dichloroacetophenone, 2-bromo-3',5'-difluoroacetophenone,2-bromo-2',6'-dichloroacetophenone,2-bromo-2',4',6'-trichloroacetophenone,2-bromo-3',4',5'-trichloroacetophenone. 4-bromoacetyl-2-methylthiazole,4-bromoacetyl-2-trifluoromethylthiazole, and so on.

Examples of the acid are Br.o slashed.nsted acids such as sulfuric acid,acetic acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonicacid, hydrogen chloride, etc.; and Lewis acids such as zinc chloride,boron trifluoride, aluminum chloride, aluminum bromide, titaniumtetrachloride, tin tetrachloride, tin trichloride, etc.

An amount of the acid is usually from 0.8 to 1.2 equivalents, preferablyfrom 0.9 to 1.1 equivalents of the metal borohydride in the mixture ofthe borane compound and the metal borohydride.

In general, the reduction reaction is performed in the presence of asolvent. Examples of the solvent are ethers (e.g. dioxane,tetrahydrofuran, diglyme, etc.), sulfides (e.g. dimethylsulfide,diethylsulfide, etc.), and mixtures thereof, and mixtures of the abovesolvent and a hydrocarbon (e.g. benzene, toluene, xylene, chlorobenzene,1,2-dichloroethane, etc.).

An amount of the solvent is usually from 1 to 50 wt. parts per one wt.part of the oxime derivative.

The reduction of the prochiral ketone is carried out by reacting theprochiral ketone and the acid with the mixture of the metal borohydrideand the borane compound or the optically active oxazaborolidine (II).Preferably, the prochiral ketone and the acid are dropwise added to themixture of the metal borohydride and the borane compound or theoptically active oxazaborolidine (II). In this case, the prochiralketone and the acid may be added in admixture or separately.Alternatively, they may be added in the form of a solution in thesolvent.

A reducing temperature is usually 150° C. or lower, preferably from -20°to 110° C., more preferably 0° to 100° C.

A time for dropwise adding the prochiral ketone and the acid is usuallyfrom 0.1 to 20 hours. After the dropwise addition of the prochiralketone and the acid, the reaction mixture is preferably stirred for 0.1to 10 hours while warming at a temperature in the above range.

The progress of the reaction can be monitored with an analytical methodsuch as gas chromatography.

After the reduction reaction, the borane compound or the opticallyactive oxazaborolidine (II) may be decomposed by the addition of an acidsuch as hydrochloric acid to the reaction mixture, and optionally thesolvent is evaporated off. Then, to the reaction mixture, an extractionsolvent such as toluene and an aqueous solution of an acid such ashydrochloric acid are added to separate an acid of the optically activeβ-aminoalcohol (I) with the acid, and the solvent is evaporated off fromthe separated organic layer to obtain the desired optically activealcohol in the salt form.

The separated salt of the optically active β-aminoalcohol (I) with theacid is made basic and extracted with an extraction solvent such astoluene, followed by evaporating the solvent off to recover theoptically active β-aminoalcohol (I) in the free form.

The obtained optically active alcohol can be further purified by a perse conventional purification method such as distillation,chromatography, and so on.

Preparation of an optically active amine (III) by reduction of an oximederivative (IV)

The optically active amine (III) can be prepared by reacting the oximederivative (IV) and the acid with the mixture of the metal borohydrideand

i) the borane compound prepared from the optically active β-aminoalcohol(I) and the boron hydride, or from the optically active β-aminoalcohol(I), the metal borohydride and the acid, or

ii) the optically active oxazaborolidine (II).

The oxime derivative (IV) may be an syn-form, an anti-form or a mixturethereof which is rich in one of them.

In the formula (IV), R⁷ and R⁸ are different and represent an alkylgroup which may have at least one substituent, an aryl group which mayhave at least one substituent or an aralkyl group which may have atleast one substituent, or R⁷ and R⁸ form, together with the carbon atomof the oxime group, a ring or condensed ring which may have a heteroatom.

Examples of the groups for each of R⁷ and R⁸ are the same as thoseexemplified in connection with the prochiral ketone (VI).

Examples of the ring or condensed ring formed from R⁷ and R⁸ togetherwith the carbon atom of the oxime group are oxime ethers of cyclicketones (e.g. cyclopentenone, cyclohexenone, etc.), cyclic ketoneshaving a hetero atom (e.g. 3-oxopyrrolidine, 3-oxopiperidine,3-oxoquinuclidine, N-alkyl or N-aralkyl derivatives thereof, etc.), andbenzene-ring condensed cyclic ketones (e.g. indanone, tetralinone,etc.).

The alkyl group for R⁹ has usually 1 to 10 carbon atoms, and examplesthereof are methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl,cyclohexyl, heptyl, cycloheptyl, octyl, nonyl, decyl, etc.

The aralkyl group for R⁹ has usually 7 to 12 carbon atoms, and examplesthereof are benzyl, β-phenethyl, naphthylmethyl, etc.

The alkyl-substituted silyl group has usually 3 to 12 carbon atoms inthe alkyl substituents in total, and examples thereof aretrimethylsilyl, dimethyl-tert.-butylsilyl, tri-n-propylsilyl,tri-n-butylsilyl, etc.

Specific examples of the oxime derivative (IV) are O-methyl, O-ethyl,O-octyl, O-cyclohexyl, O-benzyl, and O-trimethylsilyl derivatives ofoximes of acetophenone, propiophenone, butyrophenone, 1-acetonaphthone,2-acetonaphthone, o-, m- or p-methoxyacetophenone, o-ethoxyacetophenone,o-propoxyacetophenone, o-, m- or p-benzyloxyacetophenone,2-acetylpyridine, p-cyanoacetophenone, phenyl benzyl ketone, phenylo-tolylmethyl ketone, phenyl m-tolylmethyl ketone, phenyl p-tolylmethylketone, 2-butanone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone,cyclohexyl methyl ketone, cyclohexyl benzyl ketone,2-chloroacetophenone, p-tert.-butylacetophenone, p-chloroacetophenone,m-bromoacetophenone, p-bromoacetophenone, p-cyanoacetophenone,2-chloro-3'-chloroacetophenone, m,p- or o,p-dichloroacetophenone,3-sulfonamide-4-methoxybenzyl methyl ketone, 3,4-dimethoxybenzyl methylketone, 3'-benzyloxyacetophenone, isobutyl 2-piperidinophenyl ketone,cyclopentenone, cyclohexenone, pyrrolidin-2-one, pyrrolidin-3-one,piperidin-2-one, piperidin-3-one, quinuclidin-2-one, quinuclidin-3-one,2-piperidylmethyl phenyl ketone, 8-methoxytetrahydronaphthalen-2-one,etc.

They may be the syn- or anti-form, or mixtures thereof in which eitherone of the syn-form and the anti-form is richer than the other.

The oxime derivative (IV) may be prepared from the above describedprochiral ketone (III) according to a per se conventional method. Whenone of the syn-form and the anti-form, is used, the rest of them may betransformed to the necessary form by isomerization between the anti-formand the syn-form, whereby the raw material is effectively used.

Examples of the acid are Br.o slashed.nsted acids such as sulfuric acid,acetic acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonicacid, hydrogen chloride, etc.; and Lewis acids such as zinc chloride,boron trifluoride, aluminum chloride, aluminum bromide, titaniumtetrachloride, tin tetrachloride, tin trichloride, iodine, etc.

An amount of the acid is usually from 0.8 to 1.2 equivalents, preferablyfrom 0.9 to 1.1 equivalents of the metal borohydride.

In general, the reduction reaction is performed in the presence of asolvent. Examples of the solvent are ethers (e.g. dioxane,tetrahydrofuran, diglyme, etc.), sulfides (e.g. dimethylsulfide,diethylsulfide, etc.), and mixtures thereof, and mixtures of the abovesolvent and a hydrocarbon (e.g. benzene, toluene, xylene, chlorobenzene,1,2-dichloroethane, etc.).

An amount of the solvent is usually from 1 to 50 times the weight of theoxime derivative (III).

The reduction of the oxime derivative (IV) is carried out by reactingthe oxime derivative (IV) and the acid with the mixture of the metalborohydride and the borane compound or the optically activeoxazaborolidine (II). Preferably, the oxime derivative (IV) and the acidis added to the mixture of the metal borohydride and the borane compoundor the optically active oxazaborolidine (II). In this case, they may beadded in admixture or separately, or in the form of a solution in thesolvent.

The reduction reaction can be accelerated by the use of a transitionmetal halide (e.g. cobalt chloride, nickel chloride, cesium chloride,etc.) in an amount of 0.1 to 5 mole % based on the oxime derivative(IV).

A reaction temperature is usually 150° C. or lower, preferably from -20°to +110° C., more preferably from 0° to 100° C.

A time for adding the oxime derivative and the acid is usually from 0.1to 10 hours. After the addition of the oxime derivative and the acid,the reaction mixture is preferably stirred for 1 to 30 hours whilewarming at a temperature in the above range.

The progress of the reaction can be monitored with an analytical methodsuch as gas chromatography.

After the reduction reaction, the borane compound or the opticallyactive oxazaborolidine (II) may be decomposed by the addition of an acidsuch as hydrochloric acid to the reaction mixture, to obtain theoptically active β-aminoalcohol (I) and the optically active amine(III), which are separated by utilizing a difference of theirsolubilities in a solvent, or distillation.

The obtained optically active amine (I) can be further purified by a perse conventional purification method such as recrystallization in theform of a salt with the acid, distillation, chromatography, and so on.

The optically active β-aminoalcohol separated can be recovered in thesame manner as in the above chapter of "Preparation of optically activealcohol".

According to the present invention, the optically active alcohol havinga high optical purity can be prepared by using the metal borohydridewhich is cheap and available in an industrial scale as a hydrogensource.

In addition, the amount of the used metal borohydride or boron hydrideis decreased and the optically active alcohol is effectively prepared.

Further, the optically active amine is prepared effectively withdecreasing the used amount of the metal borohydride or boron hydride asthe hydrogen source.

EXAMPLES

The present invention will be illustrated by the following Examples,which will not limit the scope of the present invention in any way.

Example 1

Under a nitrogen atmosphere, sodium borohydride (0.38 g, 10 mmol) wassuspended in a solution of (1S,2R)-(+)-norephedrine (0.151 g, 1 mmol) indioxane (10 ml). To the suspension, a mixture of 96% sulfuric acid(0.102 g, 1 mmol) and dioxane (1 ml) was added, followed by stirring at65° to 70° C. for 30 minutes to obtain a mixture of a borane compoundand sodium borohydride.

To this mixture, a mixture of 96% sulfuric acid (0.408 g, 4 mmol),acetophenone (2.16 g, 18 mmol) and dioxane (20 ml) was dropwise addedover 100 minutes at the same temperature, and then stirred for 30minutes.

After cooling to room temperature, the 10% hydrochloric acid (20 ml) wasadded, and then the mixture was extracted with toluene (each 20 ml)twice. The organic layer was washed with water (each 20 ml) twice, andanalyzed by gas chromatography to find that the conversion was 100%. Thewashed extract was also analyzed by high performance liquidchromatography (HPLC) using an optically active column to find thatobtained optically active α-phenethyl alcohol consisted of 10.4% of the(R)-isomer and 89.6 % of the (S)-isomer.

Example 2

In the same manner as in Example 1 except that a mixture of 96% sulfuricacid (0.408 g, 4 mmol), acetophenone (2.16 g, 18 mmol) and dioxane (10ml) was dropwise added while refluxing dioxane (101° C.), the reactionswere performed.

The conversion was 100%, and the obtained optically active α-phenethylalcohol consisted of 12.2% of the (R)-isomer and 87.8% of the(S)-isomer.

Example 3

In the same manner as in Example 1 except that tetrahydrofuran was usedin place of dioxane, and the mixture was stirred for 30 minutes whilerefluxing tetrahydrofuran (65° C.) instead of the stirring at 65°-70° C.for 30 minutes, a mixture of the borane compound and sodium borohydridewas prepared.

Then, in the same manner as in Example 1 except that a mixture of 96%sulfuric acid (0.408 g, 4 mmol), acetophenone (1.2 g, 10 mmol) andtetrahydrofuran (6 ml) was dropwise added over 60 minutes at the sametemperature, and thereafter a mixture of acetophenone (1.2 g, 10 mmol)and tetrahydrofuran (6 ml) was dropwise added over 60 minutes, thereaction was performed.

The conversion was 92%, and the obtained optically active α-phenethylalcohol consisted of 14.3% of the (R)-isomer and 85.7% of the(S)-isomer.

Example 4

In the same manner as in Example 1 except that(1R,2S)-2-amino-1,2-diphenylethanol (0.213 g, 1 mmol) was(1S,2R)-(+)-norephedrine, the reactions were performed.

The conversion was 100%, and the obtained optically active α-phenethylalcohol consisted of 6.4% of the (R)-isomer and 93.6% of the (S)-isomer.

Example 5

In the same manner as in Example 1 except that(S)-α,α-diphenyl-2-pyrrolidinemethanol (0.253 g, 1 mmol) was used inplace of (1S,2R)-(+)-norephedrine, the reactions were performed.

The conversion was 100%, and the obtained optically active α-phenethylalcohol consisted of 3.2% of the (R)-isomer and 96.8% of the (S)-isomer.

Example 6

Under a nitrogen atmosphere, sodium borohydride (0.378 g, 10 mmol) wassuspended in a solution of (1S,2R)-(+)-norephedrine (0.1512 g, 1 mmol)in dioxane (10 ml). To the suspension, a mixture of 100% sulfuric acid(0.098 g, 1 mmol) and dioxane (1 ml) was added over 10 minutes, followedby stirring at 75° to 80° C. for 1 hour to obtain a mixture of a boranecompound and sodium borohydride.

To this mixture, a mixture of 100% sulfuric acid (0.392 g, 4 mmol),phenacyl chloride (1.546 g, 10 mmol) and dioxane (5 ml) was dropwiseadded over 15 minutes at the same temperature, and then stirred for 30minutes at the same temperature.

After cooling to room temperature, the 10% hydrochloric acid (10 ml) wasadded, and then the mixture was extracted with toluene (each 20 ml)twice. The organic layer was washed with water (each 30 ml) twice toobtain a solution of optically active 2-chloro-1-phenylethanol intoluene.

The conversion was 100%, and the obtained optically active2-chloro-1-phenylethanol consisted of 87.3% of the (R)-isomer and 12.7%of the (S)-isomer.

Example 7

In the same manner as in Example 6 except that(1S,2R)-2-amino-1-(2,5-dimethoxyphenyl)-1-propanol (1 mmol) was used inplace of (1S,2R)-(+)-norephedrine, the reactions were performed.

The conversion was 100%, and the obtained optically active2-chloro-1-phenylethanol consisted of 84.6% of the (R)-isomer and 15.4%of the (S)-isomer.

Example 8

In the same manner as in Example 6 except that(1S,2R)-2-amino-1-(2,5-dimethylphenyl)-1-propanol (1 mmol) was used inplace of (1S,2R)-(+)-norephedrine, the reactions were performed.

The conversion was 100%, and the obtained optically active2-chloro-1-phenylethanol consisted of 82.7% of the (R)-isomer and 17.3%of the (S)-isomer.

Example 9

In the same manner as in Example 6 except that(1S,2R)-1,2-diphenyl-2-aminoethanol (1 mmol) was used in place of(1S,2R)-(+)-norephedrine, the reactions were performed.

The conversion was 100%, and the obtained optically active2-chloro-1-phenylethanol consisted of 84.5% of the (R)-isomer and 15.5%of the (S)-isomer.

Example 10

In the same manner as in Example 6 except that propiophenone was used inplace of phenacyl chloride, 98% sulfuric acid was used in place of 100%sulfuric acid, and the mixture of the 98% sulfuric acid (4 mmol),propiophenone (10 mmol) and dioxane (5 ml) was dropwise added over 30minutes, the reactions were performed.

The conversion was 100%, and the obtained optically active2-chloro-1-phenylpropanol consisted of 19% of the (R)-isomer and 81% ofthe (S)-isomer.

Example 11

Under a nitrogen atmosphere, a solution of 1M boranetetrahydrofurancomplex (2 ml, 2 mmol) in tetrahydrofuran was added to a solution of(1S,2R)-(+)-norephedrine (0.1512 g, 1 mmol) in dioxane (8 ml) at 10° to120° C., followed by stirring at 75° to 80° C. for 1 hour to obtain aborane compound.

In the borane compound solution, sodium borohydride (0.303 g, 8 mmol)was suspended at 45° to 50° C., and then, to the suspension, a mixtureof 98% sulfuric acid (0.4 g, 4 mmol), propiophenone (1.342 g, 10 mmol)and dioxane (5 ml) was added over 35 minutes, followed by stirring atthe same temperature for 30 minutes. Thereafter, the reaction mixturewas post-treated in the same manner as in Example 6.

The conversion was 99.9%, and the obtained optically active1-phenylpropanol consisted of 18.3% of the (R)-isomer and 81.7% of the(S)-isomer.

Example 12

Under a nitrogen atmosphere, sodium borohydride (0.0908 g, 2.4 mmol) wassuspended in a solution of (R)-(-)-phenylglycinol (0.0274 g, 0.2 mmol)in tetrahydrofuran (10 ml). To the suspension, a solution of iodine(0.203 g, 0.8 mmol) in tetrahydrofuran (1 ml) was added over about 10minutes, followed by stirring at 65° C. for 1.75 hours to obtain amixture of a borane compound and sodium borohydride.

To this mixture, a mixture of iodine (0.203 g, 0.8 mmol), acetophenone(0.24 g, 2 mmol) and tetrahydrofuran (1 ml) was dropwise added over 25minutes, and stirred for 30 minutes at the same temperature.

After cooling to room temperature, the 10% hydrochloric acid (10 ml) wasadded, and then the mixture was extracted with toluene (each 20 ml)twice. The organic layer was washed with water (each 20 ml) twice toobtain a solution of optically active α-phenethyl alcohol in toluene.

The conversion was above 99.9%, and the obtained optically active(x-phenethyl alcohol consisted of 94.4% of the (R)-isomer and 5.6% ofthe (S)-isomer.

Example 13

In the same manner as in Example 13 except that (1S,2R)-(+)-norephedrine(0.2 mmol) was used in place of (R)-(-)-phenylglycinol, the reactionswere performed.

The conversion was above 99.9%, and the obtained optically activeα-phenethyl alcohol consisted of 89.4% of the (R)-isomer and 10.6% ofthe (S)-isomer.

Comparative Example 1

In the same manner as in Example 10 except that a mixture of 98%sulfuric acid (4 mmol) and dioxane (4 ml) was dropwise added over 10minutes in place of dropwise addition of the mixture of 98% sulfuricacid (4 mmol), propiophenone (10 mmol) and dioxane (5 ml) over 30minutes, and the mixture of propiophenone (10 mmol) and dioxane (2 ml)was dropwise added over 10 minutes, and thereafter the mixture wasstirred for 1.5 hours, the reactions were performed.

The conversion was 2.7%, and the obtained optically active1-phenylpropanol consisted of 40.4% of the (R)-isomer and 59.6% of the(S)-isomer.

Example 14

Under a nitrogen atmosphere, sodium borohydride (0.167 g, 4.4 mmol) wassuspended in a solution of(R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (0.1224 g,0.44 mmol) in dioxane (5 ml) (manufactured by Aldrich). To thesuspension, a mixture of 98% sulfuric acid (0.221 g, 2.2 mmol),propiophenone (0.651 g, 4.9 mmol) and dioxane (2.5 ml) was added over 30minutes at 75° to 80° C., followed by stirring at the same temperaturefor 30 minutes.

After the above reaction, the 10% hydrochloric acid (8 ml) was added,and then the mixture was extracted with toluene (each 15 ml) twice. Theorganic layer was washed with water (each 20 ml) twice, and analyzed bygas chromatography to find that the conversion was 99.9%. The washedorganic layer was also analyzed by high performance liquidchromatography (HPLC) using an optically active column to find thatobtained optically active 1-phenyl-1-propanol consisted of 11.3% of the(R)-isomer and 88.7% of the (S)-isomer.

Comparative Example 2

In the same manner as in Example 14 except that the mixture of 98%sulfuric acid (2.2 mmol) and dioxane (1.5 ml) was dropwise added over 20minutes instead of the dropwise addition of the mixture of 98% sulfuricacid (2.2 mmol), propiophenone (4.9 mmol) and dioxane (2.5 ml) over 30minutes, and then the solution of propiophenone (4.9 mmol) in dioxane(1.5 ml) was dropwise added over 10 minutes, the reactions wereperformed.

The conversion was 2.6%, and the obtained optically active1-phenylpropanol consisted of 48.2% of the (R)-isomer and 51.8% of the(S)-isomer.

Example 15

Under a nitrogen atmosphere, sodium borohydride (0.38 g, 10 mmol) wassuspended in a solution of (1S,2R)-norephedrine (0.68 g, 4.5 mmol) in amixed solvent of toluene and tetrahydrofuran (volume ratio=1:1) (10 ml)at room temperature. To the suspension, a solution of 100% sulfuric acid(0.245 g, 2.5 mmol) in a mixed solvent of toluene and tetrahydrofuran(volume ratio=1:1) (2.5 ml) was added over 20 minutes at roomtemperature, followed by stirring at 70° to 75° C. for 1 hour to obtaina mixture of a borane compound and sodium borohydride.

To this mixture, a solution of 100% sulfuric acid (0.245 g, 2.5 mmol)and anti-2',4'-dichloroacetophenone(O-methyl)oxime (1.09 g, 5 mmol) in amixed solvent of toluene and tetrahydrofuran (volume ratio=1:1) (2.5 ml)was dropwise added over 30 minutes at 45° to 50° C., and stirred for 14hours at the same temperature and then for 8 hours at 75° to 80° C.

After cooling to room temperature, the 10% hydrochloric acid (10 ml) wasadded, and then the mixture was made alkaline by the addition of a 20%aqueous solution of sodium hydroxide. Then, the mixture was extractedwith toluene (each 15 ml) twice, and the organic layer was washed withwater (each 15 ml) twice to obtain a solution of optically active(α-2',4'-dichlorophenylethylamine in toluene.

The conversion was 96.7%, and the obtained product contained 85.5% ofα-2',4'-dichlorophenylethylamine and 14.5% ofN-methoxy-α-2',4'-dichlorophenylethylamine. The optically activeα-2',4'-dichlorophenylethylamine consisted of 93% of the (R)-isomer and7% of the (S)-isomer.

Example 16

Under a nitrogen atmosphere, sodium borohydride (1.665 g, 0.044 mol) wassuspended in a solution of (1S,2R)-norephedrine (6.05 g, 0.04 mol) intetrahydrofuran (50 ml), and cooled to 10° C. To the suspension, asolution of 100% sulfuric acid (2.157 g, 0.022 mol) in tetrahydrofuran(50 ml) was added over 40 minutes at 10 to 15° C. Toluene (50 ml) wasadded and then the mixture was stirred at 70° to 75° C. for 1 hour toobtain a borane compound.

To this mixture which was cooled to 45° C., sodium borohydride (2.118 g,0.056 g) was added and then a solution of 100% sulfuric acid (2.754 g,0.028 ml) and anti-2',4'-dichloroacetophenone(O-methyl)oxime (10.9 g,0.05 mol) in a mixed solvent of toluene and tetrahydrofuran (volumeratio=1:1) (30 ml) was dropwise added over 40 minutes at 45 to 50° C.,and stirred for 3 hours at the same temperature and then for 8 hours at75° to 80° C. Thereafter, cobalt chloride (0.0325 g) was added, and themixture was further stirred for 3 hours at the same temperature.

After cooling to room temperature, the 10% hydrochloric acid (40 ml) wasadded, and then the mixture was made alkaline by the addition of a 20%aqueous solution of sodium hydroxide. Then, the mixture was extractedwith toluene (each 40 ml) twice, and the organic layer was washed withwater (each 40 ml) twice to obtain a solution of optically activeα-2',4'-dichlorophenylethylamine in toluene.

The conversion was 98.3%, and the obtained product contained 99.8% ofα-2',4'-dichlorophenylethylamine and 0.2% ofN-methoxy-α-2',4'-dichlorophenylethylamine. The optically activeα-2',4'-dichlorophenylethylamine consisted of 90.7% of the (R)-isomerand 9.3% of the (S)-isomer.

Example 17

In the same manner as in Example 15 except that(1S,2R)-2-amino-1,2-diphenylethanol (0.96 g, 4.5 mmol) was used in placeof (1S,2R)-norephedrine, the reactions were performed.

The conversion was above 99.9%, and the obtained product contained 96.4%of the amine compound and 3.6% of the N-methoxy derivative. Theoptically active compound consisted of 85.4% of the (R)-isomer and 14.6%of the (S)-isomer.

Example 18

In the same manner as in Example 15 except that(1S,2R)-2-amino-1-(2,5-dimethoxyphenyl)propanol (0.89 g, 4.5 mmol) wasused in place of (1S,2R)-norephedrine, the reactions were performed.

The conversion was 97.2%, and the obtained product contained 96.6% ofthe amine compound and 3.4% of the N-methoxy derivative. The opticallyactive compound consisted of 86.5% of the (R)-isomer and 13.5% of the(S)-isomer.

Example 19

In the same manner as in Example 15 except that(1S,2R)-2-amino-1-(2,5-dimethylphenyl)propanol (0.81 g, 4.5 mmol) wasused in place of (1S,2R)-norephedrine, the reactions were performed.

The conversion was 96.3%, and the obtained product contained 96.8% ofthe amine compound and 3.2% of the N-methoxy derivative. The opticallyactive compound consisted of 81.9% of the (R)-isomer and 18.1% of the(S)-isomer.

Example 20

Under a nitrogen atmosphere, a solution of 1M boranetetrahydrofurancomplex (4.5 ml, 4.5 mmol) was added to a solution of(1S,2R)-norephedrine (0.605 g, 4 mmol) in tetrahydrofuran (0.510 ml) andtoluene (5 ml) at 10° to 15° C., followed by stirring at 75° to 80° C.for 1 hour to obtain a borane compound.

After cooling to room temperature, sodium borohydride (0.208 g, 5.5 mol)was added, and then a solution of 100% sulfuric acid (0.27 g, 2.75 mmol)and anti-2',4'-dichloroacetophenone(O-methyl)oxime (1.09 g, 5 mmol) in amixed solvent of toluene and tetrahydrofuran (volume ratio=1:1) (5 ml)was dropwise added over 30 minutes at 45° to 50° C., followed bystirring at the same temperature for 14.5 hours, and then at 75° to 80°C. for 10 hours.

Thereafter, the reaction mixture was post-treated and analyzed in thesame manner as in Example 15.

The conversion was 83.7%, and the obtained product contained 81.3% ofthe amine compound and 18.7% of the N-methoxy derivative. The opticallyactive compound consisted of 92.8% of the (R)-isomer and 7.2% of the(S)-isomer.

Example 21

Under a nitrogen atmosphere, sodium borohydride (0.076 g, 2 mmol) wassuspended in a solution of (1S,2R)-norephedrine (0.121 g, 0.8 mmol) in amixed solvent of toluene and tetrahydrofuran (volume ratio=1:1) (2 ml).To the suspension, a solution of 98% sulfuric acid (0.045 g, 0.45 mmol)in a mixed solvent of toluene and tetrahydrofuran (volume ratio=1:1)(0.45 ml) was added over 10 minutes at 15° to 20° C., followed bystirring at 75° to 80° C. for 1 hour to obtain a mixture of a boranecompound and sodium borohydride.

To this mixture, a solution of 98% sulfuric acid (0.055 g, 0.55 mmol)and p-tolylmethyl phenyl ketone(O-methyl)oxime (a ratio of anti-form tosyn-form=93.5:6.5) (0.239 g, 1 mmol) in a mixed solvent of toluene andtetrahydrofuran (volume ratio=1:1) (0.55 ml) was dropwise added over 20minutes at 45° to 50° C., and stirred for 19.5 hours at the sametemperature and then for 10 hours at 75° to 80° C.

Thereafter, the reaction mixture was post-treated and analyzed in thesame manner as in Example 15.

The conversion was 90.8%, and the obtained product contained 95.6% of2-(p-tolyl)-1-phenylethylamine and 4.4% ofN-methoxy-2-(p-tolyl)-1-phenylethylamine. The optically active2-(p-tolyl)-1-phenylethylamine consisted of 88.9% of the (R)-isomer and11.1% of the (S)-isomer.

Example 22

Under a nitrogen atmosphere, sodium borohydride (0.32 g, 8.5 mmol) wassuspended in a solution of (R)-2-amino-1,1,3-triphenyl-1-propanol (0.68g, 2.0 mmol) in a mixed solvent of toluene and tetrahydrofuran (volumeratio=1:1) (10 ml). To the suspension which was cooled to 10° C., asolution of 100% sulfuric acid (0.07 g, 0.75 mmol) in a mixed solvent oftoluene and tetrahydrofuran (volume ratio=1:1) (1 ml) was added over 30minutes at 10° to 15° C., followed by stirring at 45° to 50° C. for 1hour to obtain a mixture of a borane compound and sodium borohydride.

To this mixture, a solution of 100% sulfuric acid (0.34 g, 3.5 mmol) andanti-2',4'-dichloroacetophenone(O-methyl)oxime (1.09 g, 5 mmol) in amixed solvent of toluene and tetrahydrofuran (volume ratio=1:1) (2.0 ml)was dropwise added over 30 minutes at 45° to 50° C., and stirred for 5hours at the same temperature and then for 14 hours at 75° to 80° C.

After cooling to room temperature, the 10% hydrochloric acid (10 ml) wasadded, and then the mixture was made alkaline by the addition of a 20%aqueous solution of sodium hydroxide. Then, the mixture was extractedwith toluene (each 15 ml) twice, and the organic layer was washed withwater (each 15 ml) twice.

The conversion was 100%, and the product contained 99.9% ofα-2',4'-dichlorophenylethylamine and 0.1% ofN-methoxy-α-2',4'-dichlorophenylethylamine.

The optically active α-2',4'-dichlorophenylethylamine consisted of 97.1%of the (R)-isomer and 2.9% of the (S)-isomer.

Example 23

In the same manner as in Example 22 except that(S)-2-amino-3-methyl-1,1-diphenyl-1-butanol (0.38 g, 1.5 mmol) was usedin place of (R)-2-amino-1,1,3-triphenyl-1-propanol, the reactions wereperformed.

The conversion was 97.9%, and the obtained product contained 93.7% ofthe amine compound and 6.3% of the N-methoxy derivative. The opticallyactive compound consisted of 97.0% of the (S)-isomer and 3.0% of the(R)-isomer.

Example 24

In the same manner as in Example 22 except that(S)-2-amino-4-methyl-1-pentanol (0.17 g, 1.5 mmol) was used in place of(R)-2-amino-1,1,3-triphenyl-1-propanol, the reactions were performed.

The conversion was 97.2%, and the obtained product contained 93.1% ofthe amine compound and 6.9% of the N-methoxy derivative. The opticallyactive compound consisted of 90.5% of the (S)-isomer and 9.5% of the(R)-isomer.

Example 25

In the same manner as in Example 22 except that(S)-2-amino-3-methyl-1-butanol (0.16 g, 1.5 mmol) was used in place of(R)-2-amino-1,1,3-triphenyl-1-propanol, the reactions were performed.

The conversion was 97.6%, and the obtained product contained 86.2% ofthe amine compound and 13.8% of the N-methoxy derivative. The opticallyactive compound consisted of 89.4% of the (S)-isomer and 10.6% of the(R)-isomer.

Example 26

Under a nitrogen atmosphere, sodium borohydride (0.32 g, 8.5 mmol) wassuspended in a solution of (R)-2-amino-1,1-diphenyl-1-propanol (0.45 g,2.0 mmol) in a mixed solvent of toluene and tetrahydrofuran (volumeratio=1:1) (10 ml). To the suspension which was cooled to 10° C., asolution of 100% sulfuric acid (0.07 g, 0.75 mmol) in a mixed solvent oftoluene and tetrahydrofuran (volume ratio=1:1) (1 ml) was added over 30minutes at 10 to 15° C., followed by stirring at 45° to 50° C. for 1hour to obtain a mixture of a borane compound and sodium borohydride.

To this mixture, a solution of 100% sulfuric acid (0.34 g, 3.5 mmol) andanti-2',4'-dichloroacetophenone(O-methyl)oxime (1.09 g, 5 mmol) in amixed solvent of toluene and tetrahydrofuran (volume ratio=1:1) (2.0 ml)was dropwise added over 30 minutes at 45° to 50° C., and stirred for 5hours at the same temperature and then for 14 hours at 75° to 80° C.

After cooling to room temperature, the 10% hydrochloric acid (10 ml) wasadded, and then the mixture was made alkaline by the addition of a 20%aqueous solution of sodium hydroxide. Then, the mixture was extractedwith toluene (each 15 ml) twice, and the organic layer was washed withwater (each 15 ml) twice.

The conversion was 100%, and the product contained 99.9% of the aminecompound and 0.1% of the N-methoxy derivative.

The optically active amine compound consisted of 97.1% of the (R)-isomerand 2.9% of the (S)-isomer.

Example 27

Under a nitrogen atmosphere, sodium borohydride (0.378 g, 10.0 mmol) wassuspended in a solution of (R)-2-amino-1,1-diphenyl-1-propanol (0.909 g,4.0 mmol) in tetrahydrofuran (10 ml). To the suspension which was cooledto 10° C., a solution of 100% sulfuric acid (0.22 g, 2.25 mmol) intetrahydrofuran (1 ml) was added over 30 minutes at 10° to 15° C.,followed by stirring at 45° to 50° C. for 1 hour to obtain a mixture ofa borane compound and sodium borohydride.

To this mixture, toluene (5 ml) was dropwise added over 30 minutes atthe same temperature, and then a solution of 100% sulfuric acid (0.27 g,2.75 mmol) and 3'-methoxyacetophenone(O-methyl)oxime (a ratio ofanti-form to syn-form=98.4:1.6) (0.896 g, 5 mmol) in a mixed solvent oftoluene and tetrahydrofuran (volume ratio=2:1) (3.0 ml) was dropwiseadded over 45 minutes, and stirred for 19.5 hours at the sametemperature and then for 7.5 hours at 75° to 80° C.

After cooling to room temperature, the 10% hydrochloric acid (10 ml) wasadded, and then the mixture was made alkaline by the addition of a 23%aqueous solution of sodium hydroxide. Then, the mixture was extractedwith n-hexane (each 15 ml) twice, and the organic layer was washed withwater (each 15 ml) twice.

The conversion was 99.9%, and the product contained 99.9% ofα-3'-methoxyphenylethylamine and 0.1% ofN-methoxy-α-3'-methoxyphenylethylamine.

The optically active α-3'-methoxyphenylethylamine consisted of 95.9% ofthe (R)-isomer and 4.1% of the (S)-isomer.

Example 28

In the same manner as in Example 27 except that(1S,2R)-2-amino-1-phenyl-1-propanol (0.605 g, 4.0 mmol) was used inplace of (R)-2-amino-1,1-diphenyl-1-propanol, the reactions wereperformed.

The conversion was 99.3%, and the obtained product contained 89.0% ofthe amine compound and 11.0% of the N-methoxy derivative. The opticallyactive compound consisted of 92.7% of the (R)-isomer and 7.3% of the(S)-isomer.

Example 29

In the same manner as in Example 27 except that(R)-2-amino-2-phenylethanol (0.605 g, 4.0 mmol) was used in place of(R)-2-amino-1,1-diphenyl-1-propanol, the reactions were performed.

The conversion was 95.3%, and the obtained product contained 98.6% ofthe amine compound and 1.4% of the N-methoxy derivative. The opticallyactive compound consisted of 89.1% of the (R)-isomer and 10.9% of the(S)-isomer.

Example 30

Under a nitrogen atmosphere, sodium borohydride (0.121 g, 3.2 mmol) wassuspended in a solution of(R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (0.333 g,1.2 mmol) in a mixed solvent of toluene and tetrahydrofuran (volumeratio of 1:1) (5 ml) (manufactured by Aldrich). To the suspension, asolution of 98% sulfuric acid (0.16 g, 1.6 mmol) and anti-phenyl p-tolylketone(O-methyl)oxime (ratio of anti-form to syn-form=93.5:6.5) (0.383g, 1.6 mmol) in a mixed solvent of toluene and tetrahydrofuran (volumeratio of 1:1) (3 ml) was added over 30 minutes at 45° to 50° C.,followed by stirring at the same temperature for 4 hours, and then at75° to 80° C. for 24 hours.

After the above reaction, the 10% hydrochloric acid (8 ml) was added,and then the mixture was extracted with toluene (each 10 ml) twice. Theorganic layer was washed with water (each 15 ml) twice to obtain asolution of (R)-1-phenyl-2-(p-tolyl)ethylamine in toluene.

The product was analyzed by gas chromatography to find that theconversion was 69.8% and the selectivity was 90.1%. The product was alsoanalyzed by high performance liquid chromatography (HPLC) using anoptically active column to find that obtained the optical purity was51%(R).

Comparative Example 1

In the same manner as in Example 30 except that a solution of 98%sulfuric acid (1.6 mmol) in a mixed solvent of toluene andtetrahydrofuran (volume ratio of 1:1) (3 ml) was dropwise added over 30minutes instead of the dropwise addition of the solution of 98% sulfuricacid (1.6 mmol) and anti-phenyl p-tolyl ketone(O-methyl)oxime (1.6 mmol)in a mixed solvent of toluene and tetrahydrofuran (volume ratio of 1:1)(1 ml), the reactions were performed.

The conversion was 50.9%, the selectivity was 76.5%, and the opticalpurity was 47.4%(R).

What is claimed is:
 1. A process for preparing an optically active amineof the formula: (III): ##STR6## wherein R⁷ and R⁸ are different andrepresent an alkyl group which may have at least one substituent, anaryl group which may have at least one substituent or an aralkyl groupwhich may have at least one substituent, or R⁷ and R⁸ form, togetherwith the carbon atom bonded to the amino group, a ring or condensed ringwhich may have a hetero atom, and * is the same as defined above,comprising:reacting an oxime derivative of the formula (IV): ##STR7##wherein R⁷ and R⁸ are the same as defined above, and R⁹ is an alkylgroup, an aralkyl group or an alkyl-substituted silyl group and an acidwith a mixture which comprises (1) a boron-containing compound selectedfrom the group consisting of (i) a borane compound which is obtainedfrom an optically active β-aminoalcohol of the formula (I) and a boronhydride, or obtained from said optically active β-aminoalcohol (I), ametal borohydride and an acid, and (ii) an acid, and (ii) an opticallyactive oxazaborolidine of the formula (II) and (2) a metal borohydride;wherein the optically active β-aminoalcohol of the formula (I) is asfollows: ##STR8## wherein R¹ is a hydrogen atom, a lower alkyl group oran aralkyl group which may have at least one substituent, R², R³, R⁴ andR⁵ represent independently of each other a hydrogen atom, a lower alkylgroup, an aryl group which may have at least one substituent, or anaralkyl group which may have a substituent, provided that R⁴ and R⁵ aredifferent, that R¹ and R⁵ may together form a lower alkylene group, orthat R³ and R⁴ may together form a lower alkylene group which mayoptionally have a substituent or with which a benzene ring is condensed,and * stands for an asymmetric carbon atom, and a boron hydride, andwherein the optically active oxazaborolidine of the formula (II) is asfollows: ##STR9## wherein R¹, R², R³, R⁴, R⁵ and * are the same asdefined above, and R⁶ is a hydrogen atom, a halogen atom, an alkyl groupwhich may be substituted by at least one halogen atom, an aryl groupwhich may have at least on substituent or an aralkyl group which mayhave at least one substituent.
 2. The process according to claim 1,wherein said oxime derivative (IV) is a syn-form, an anti-form or amixture thereof which is rich one of them.
 3. The process according toclaim 1, wherein a mixture of said oxime derivative and said acid isreacted with said mixture of the borane compound and the metalborohydride.
 4. The process according to claim 1, wherein said oximederivative and said acid are added to said mixture of the boranecompound and the metal borohydride separately.
 5. The process accordingto claim 1, wherein a mixture of said oxime derivative and said acid isreacted with said mixture of the optically active oxazaborolidine andthe metal borohydride.
 6. The process according to claim 1, wherein saidoxime derivative and said acid are added to said mixture of theoptically active oxazaborolidine and the metal borohydride separately.7. The process according to claim 1, wherein R⁷ and R⁸ are groupsselected from the group consisting of an alkyl group which may have ansubstituent and an aryl group which may have a substituent.
 8. Theprocess according to claim 7, wherein R⁷ and R⁸ are groups selected fromthe group consisting of alkyl groups, halogenated alkyl groups, arylgroups, haloaryl groups, alkoxyalkyl-substituted aryl groups andaralkyloxy-substituted aryl groups.
 9. The process according to claim 1,wherein said acid to be used together with said oxime derivative (IV) isat least one acid selected from the group consisting of Bronsted acidsand Lewis acids.